This R01 application is for five years of funding to develop, evaluate and apply novel computational tools for the purpose of understanding morphometric changes in neuroanatomical structures related to schizophrenia. Shape measures are of interest in schizophrenia because this disorder is viewed by some as a neurodevelopmental in origin and because there is evidence to suggest that during morphogenesis of the brain, abnormal pressures and/or tissue formations likely change the shape of brain structures, particularly those in the midline of the brain, as well as influencing folding patterns of the neocortex. We believe that computational morphometry tools are critical to characterize and to quantify shape changes accurately. In fact, neuroscience research as a whole has shown a growing interest in computer assisted shape studies for numerous conditions including, but not limited to, normal neurodevelopment, Alzheimer's disease, schizophrenia and schizotypal personality disorder (SPD), bipolar disorder, psychotic affective disorder, and fetal alcohol exposure. Our primary objective is thus to develop further new image analysis techniques to enable the detection and localization of shape differences between populations. We will apply this new technology to selected brain structures in first episode schizophrenic subjects compared to first episode affective subjects (mainly manic), and normal controls. Our secondary objective is to quantitatively evaluate and compare current state-of-the-art shape analysis tools, including ours, as few algorithms have been validated. Accordingly, a synthetic data set with known shape modifications will be created to use in a control experiment. In addition, we will evaluate all shape techniques on real data with previously observed shape changes (i.e., caudate nucleus in SPDs and amygdala-hippocampus in patients with schizophrenia). Finally, in an effort to promote open science, we will make all results, data, parameters and algorithms publicly available to the scientific community. By characterizing and delineating shape abnormalities in schizophrenia, we will understand further the role of brain morphometry abnormalities in schizophrenia, a disorder that is a major public health problem, affecting close to 1% of the general population.